Drugs in Clinical Pipeline: ARRY-403

ARRY-403 [(1S)-1-[5-({3-[(2-methylpyridin-3-yl)oxy]-5-(pyridin-2-ylsulfanyl)pyridin-2-yl}amino)-1,2,4-thiadiazol-3-yl]ethane-1,2-diol] is an orally available allosteric glucokinase (GK) activator developed for the treatment of type 2 diabetes mellitus (T2DM). ARRY-403 has many favorable physicochemical characteristics (log P less than 5, molecular weight less than 500, fewer than five hydrogen bond donors, fewer than 10 hydrogen bond acceptors, high permeability) and ADME properties (low potential to cause drug–drug interactions (DDIs), a weak substrate of P-glycoprotein (P-gp), clearance by direct glucuronidation and CYP3A-mediated oxidative metabolism, data on file), but exhibits pH-dependent solubility and concentration-dependent plasma protein binding in vitro. Less than dose-proportional exposure of ARRY-403 was observed during single ascending dose studies in humans [1]. ARRY-403 holds promise for superior efficacy to other oral anti-hyperglycemic agents based on its ability to control postprandial and non-fasted blood glucose, as well as fasting blood glucose. Once a day oral therapy is predicted to provide 24-hour glycemic control in patients with mild to severe diabetes [1].

ARRY-403 potently activates human glucokinase (GK) in vitro (EC₅₀ = 79 nM at 5 mM glucose), with an S_0.5 = 0.93 mM glucose (ARRY-403 at 5 mM) and V_max = 134% compared to the no activator control. It possesses good in vitro drug-like properties (aqueous solubility, cell permeability, low potential for drug-drug interactions, low predicted hepatic clearance), and selectivity against broad panels of receptors and enzymes. 

Binding studies reveal that when ARRY-403 binds to GK, a conformational change causes both its affinity for glucose and maximal velocity to increase. Moreover, preclinical studies predicts it to be effective in “hard-to-treat” T2DM population, without contraindication or dose adjustment in patients with kidney disease or risk factors for congestive heart failure [2]. Importantly for cardiovascular safety, ARRY-403 did not cause any increases in body weight, plasma triglycerides, or plasma total cholesterol, whether used as monotherapy or in combination. The candidate demonstrated an excellent preclinical safety profile, in both in vitro selectivity assays as well as in in vivo toxicology studies including cardiovascular safety.

The activity of ARRY-403 is as follows:

EC₅₀ (GK activation assay @ 5 mM glucose) = 79 nM

Common Name: ARRY-403

Synonyms: ARRY-403; ARRY 403; ARRY 403; AMG-151; AMG 151; AMG151

IUPAC Name: (1S)-1-[5-({3-[(2-methylpyridin-3-yl)oxy]-5-(pyridin-2-ylsulfanyl)pyridin-2-yl}amino)-1,2,4-thiadiazol-3-yl]ethane-1,2-diol

CAS Number: 

Mechanism of Action: Kinase Activator; Glucokinase Activator

Indication: Treatment of Type 2 Diabetes Mellitus; Treatment of T2DM

Development Stage: Phase II

Company: Array BioPharma/Amgen

Glucokinase (GK) is an enzyme that, among other things, facilitates phosphorylation of glucose to glucose-6-phosphate. In vertebrates, GK-mediated phosphorylation generally occurs in cells in the liver, pancreas, gut, and brain. In each of these organs, GK can play a role in regulating carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising and/or falling levels of blood-glucose. Small-molecule GK activators are useful in treating type 2 diabetes because they can enhance the rate of glucose phosphorylation, and thereby reduce the amount of glucose in the blood. Therefore, GK activators lower the body's demand for insulin, especially following intake of food. In this way, GK activators provide an alternate treatment option for type 2 diabetics who otherwise may have difficulty achieving effective glycemic control. Various GK activators are known.

Glucokinase activators (GKAs) represent a promising new class of drugs for the treatment of type 2 diabetes that act directly on both the pancreas and the liver. Glucokinase (GK) is a key enzyme in glucose-sensing tissues that regulates glucose homeostatasis. GKAs lower glucose levels by enhancing the ability of pancreatic beta cells to “sense glucose” and increase insulin secretion in a glucose-dependent manner. Simultaneously, GKAs increase the uptake and disposal of glucose in the liver, while simultaneously reducing the amount it produces.

In multiple well-established in vivo models of type 2 diabetes, ARRY-403 was highly efficacious in controlling both fasting and postprandial blood glucose, with rapid onset of effect and maximal efficacy within five to eight days of once-daily dosing. Of note, ARRY-403 did not induce hypoglycemia in these diabetic animal studies. ARRY-403 was combined with existing standard-of-care drugs such as metformin, sitagliptin (a DPP-4 inhibitor), or pioglitazone (a PPARγ agonist) for additional glucose control. Importantly for cardiovascular safety, ARRY-403 did not cause any increases in body weight, plasma triglycerides, or plasma total cholesterol, whether used as monotherapy or in combination. The drug demonstrated an excellent preclinical safety profile, in both in vitro selectivity assays as well as in in vivo toxicology studies including cardiovascular safety [3].

References:

1. Chung, J.; et. al. Utilizing physiologically based pharmacokinetic modeling to inform formulation and clinical development for a compound with pH-dependent solubility. J Pharm Sci 2015, 104(4), 1522-1532.

2. Boyd, S. A.; et. al. ARRY-403, A Novel Glucokinase Activator with Potent Glucose-Dependent AntiHyperglycemic Activity in Animal Models of Type 2 Diabetes Mellitus. Poster 126-Keystone Symposium: Type 2 Diabetes and Insulin Resistance (J3), Jan 20-25, 2009, Banff, AB.
3. Boyd, S. A.; et. al. Drug Pipeline. Drug Discovery and Development Oct 2009.